Exposure to supralethal total body irradiation and transplantation of bone marrow from a DLA and pedigree-identical donor has regularly produced successful engraftment and the establishment of stable long-term chimerism in beagles of the Cooperstown colony. Bone marrow allografts performed in pairs of dogs bearing identical DLA haplotypes derived from different pedigree origins (i.e., different classes of the same haplotype) yielded two different results. Depending upon the particular haplotype pedigree combination used, such transplants either led to long-term chimerism or to failures of engraftment, secondary disease and death of the recipients (i.e., pedigree-incompatible combinations). Radiation chimeras given bone marrow from a DLA and pedigree-identical donor were challenged within 8 to 12 hrs after marrow transplantation with a renal allograft obtained from another DLA and pedigree-identical donor. The recipients have remained unresponsive to such renal allografts, and have survived indefinitely with normal renal function. In contrast, renal allografts obtained from donors bearing the same DLA haplotypes derived from pedigree-incompatible sources were rejected within 25 to 50 days after transplantation. The long-term surviving recipients have also been unresponsive to skin allografts obtained from their donor of marrow and the kidney donor. Skin grafts obtained from other DLA-and-pedigree identical dogs were rejected within 13 to 41 days, and grafts from DLA-incompatible donors survived for 10 to 25 days. These results highlight the potential importance of genetically controlled histocompatibility determinants other than DLA in conditioning allograft reactivity. The determinants uncovered in the present study appear to be linked to the DLA complex, as demonstrated by the ability of the pedigree origins of DLA haplotypes present in individual dogs to serve as an effective marker system for such non-DLA antigen(s). The results point to the potential usefulness of the early post-irradiation period for the induction of allogeneic unresponsiveness in large adult mammals.